Identification and characterization of a novel RPGR isoform in human retina

Neidhardt, John; Glaus, Esther; Barthelmes, Daniel; Zeitz, Christina; Fleischhauer, Johannes; Berger, Wolfgang

doi:10.1002/humu.20521

Cited by 43 publications

(64 citation statements)

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“…These differences might be attributed to different regulatory mechanisms due to high overexpression. In summary, these data further support previous findings of our and other groups that Rpgr is alternatively spliced and generates different isoforms in a tissue-specific manner [15,16,32]. These different isoforms might have distinct functions in the formation and maintenance of cilia and flagella.…”

Section: Isoform-specific Overexpression Of the Rpgr Transgenesupporting

confidence: 91%

“…The murine Rpgr gene consists of 19 exons and shows an extraordinary high degree of alternative splicing, similar to the human ortholog [13,15]. The predicted size of the murine protein encoded by exons 1-19 is about 95kDa, whereas an alternative isoform retaining intron 14 (equivalent to human exon ORF15) results in a protein of about 150-200 kDa.…”

Section: Introductionmentioning

confidence: 99%

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Overexpression of RPGR Leads to Male Infertility in Mice Due to Defects in Flagellar Assembly1

Brunner

Colman

Travis

et al. 2008

Biology of Reproduction

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Male infertility is one possible consequence of a group of disorders arising from dysfunction of cilia. Ciliopathies include primary ciliary dyskinesia, polycystic kidney disease, Usher syndrome, nephronophthisis, Bardet-Biedl syndrome, Alstrom syndrome, and Meckel-Gruber syndrome as well as some forms of retinal degenerations. Mutations in the retinitis pigmentosa GTPase regulator gene (RPGR) are best known for leading to retinal degeneration but have also been associated with ciliary dysfunctions affecting other tissues. To further study the involvement of RPGR in ciliopathies, transgenic mouse lines overexpressing RPGR were generated. Animals carrying the transgene in varying copy numbers were investigated. We found that infertility due to aberrant spermatozoa correlated with increased copy numbers. In animals with moderately increased gene copies of Rpgr, structural disorganization in the flagellar midpiece, outer dense fibers, and fibrous sheath was apparent. In contrast, in animals with high copy numbers, condensed sperm heads were present, but the flagellum was absent in the vast majority of spermatozoa, although early steps of flagellar biogenesis were observed. This complexity of defects in flagellar assembly suggests a role of RPGR in intraflagellar transport processes.

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Section: Isoform-specific Overexpression Of the Rpgr Transgenesupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Overexpression of RPGR Leads to Male Infertility in Mice Due to Defects in Flagellar Assembly1

Brunner

Colman

Travis

et al. 2008

Biology of Reproduction

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“…Among the different splice variants Neidhardt et al 2007;Schmid et al 2010), RPGR ex1-ORF15 and constitutive RPGR ex1-19 are the most abundantly expressed RPGR isoforms in the retina. Both proteins have been immunolocalized to photoreceptor connecting cilium of both rods and cones (Hong et al 2003;Wright et al 2011).…”

Section: Rpgr and Its Roles In The Photoreceptor Connecting Ciliummentioning

confidence: 99%

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Beltran

Cideciyan

Lewin

et al. 2014

Cold Spring Harbor Perspectives in Medicine

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“…14,16 ORF15 is a component of alternate splice variants of RPGR that are expressed predominantly in the retina, as is exon 9a. 14,20 Mutations in the RP2 gene account for approximately 15% of XLRP cases. 10,16 The RP2 gene is believed to have a role in trafficking proteins to the plasma membrane and maintaining Golgi cohesion.…”

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confidence: 99%

Mutations in the X-Linked Retinitis Pigmentosa GenesRPGRandRP2Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa

Churchill

Bowne

Sullivan

et al. 2013

Invest. Ophthalmol. Vis. Sci.

117

124

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PURPOSE. We determined the fraction of families in a wellcharacterized cohort with a provisional diagnosis of autosomal dominant retinitis pigmentosa (adRP) that have disease-causing mutations in the X-linked retinitis pigmentosa GTPase regulator (RPGR) gene or the retinitis pigmentosa 2 (RP2) gene. METHODS.Families with a provisional clinical diagnosis of adRP, and a pedigree consistent with adRP but no male-to-male transmission were selected from a cohort of 258 families, and tested for mutations in the RPGR and RP2 genes with di-deoxy sequencing. To facilitate testing of RPGR in ''adRP'' families that had no male members available for testing, the repetitive and purine-rich ORF15 of RPGR was subcloned and sequenced in heterozygous female subjects from 16 unrelated families.RESULTS. Direct sequencing of RPGR and RP2 allowed for identification of a disease-causing mutation in 21 families. Of these ''adRP'' families 19 had RPGR mutations, and two had RP2 mutations. Subcloning and sequencing of ORF15 of RPGR in female subjects identified one additional RPGR mutation. Of the 22 mutations identified, 15 have been reported previously.CONCLUSIONS. These data show that 8.5% (22 in 258) of families thought to have adRP truly have X-linked retinitis pigmentosa (XLRP). These results have substantive implications for calculation of recurrence risk, genetic counseling, and potential treatment options, and illustrate the importance of screening families with a provisional diagnosis of autosomal inheritance and no male-to-male transmission for mutations in X-linked genes. Mutations in RPGR are one of the most common causes of all forms of retinitis pigmentosa. (Invest Ophthalmol Vis Sci.

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Identification and characterization of a novel RPGR isoform in human retina

Cited by 43 publications

References 44 publications

Overexpression of RPGR Leads to Male Infertility in Mice Due to Defects in Flagellar Assembly1

Overexpression of RPGR Leads to Male Infertility in Mice Due to Defects in Flagellar Assembly1

Gene Augmentation for X-Linked Retinitis Pigmentosa Caused by Mutations in RPGR

Mutations in the X-Linked Retinitis Pigmentosa GenesRPGRandRP2Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa

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